Antigen presentation and interferon signatures in B cells driven by localized ablative cancer immunotherapy correlate with extended survival.
Antigen presentation and interferon signatures in B cells driven by localized ablative cancer immunotherapy correlate with extended survival.
复制标题
DOI：
10.7150/thno.65773
复制
发表时间：
2022
期刊：
影响因子：
12.4
通讯作者：
Chen WR
中科院分区：
文献类型：
--
作者：
Liu K;Hoover AR;Krawic JR;DeVette CI;Sun XH;Hildebrand WH;Lang ML;Axtell RC;Chen WR
基本原理：B细胞已成为保护性癌症免疫的关键调节因子。然而，在有效的免疫治疗期间在B细胞中诱导的活化途径还没有很好地理解。研究方法：我们使用了一种新的局部消融免疫疗法（LAIT），结合光热疗法（PTT）与免疫刺激剂N-二氢半乳糖壳聚糖（GC）的肿瘤内递送，治疗小鼠乳腺肿瘤病毒-多瘤中间肿瘤抗原（MMTV-PyMT）的小鼠。我们使用单细胞RNA测序来比较肿瘤微环境（TME）内的B细胞中由PTT、GC和PTT+GC诱导的转录变化。结果：与单独用PTT和GC治疗相比，LAIT显著增加了荷瘤小鼠的存活率。我们发现PTT、GC和PTT+GC增加了肿瘤浸润B细胞的比例，并诱导了与B细胞活化相关的基因表达特征。GC和PTT+GC均升高与抗原呈递相关的基因表达，而GC升高调节B细胞活化和GT3功能的转录物以及PTT+GC诱导的干扰素应答基因。轨迹分析，其中B细胞根据伪时间进程组织，揭示了GC和PTT+GC诱导B细胞从静息状态向效应表型分化。分析证实了在用PTT+GC处理后而不是用GC处理后，分化的肿瘤浸润B细胞中的干扰素特征上调。我们还观察到，如果乳腺癌患者在小鼠肿瘤中的B细胞中的基因表达升高，则乳腺癌患者具有显著更长的生存时间，所述基因表达由PTT+GC治疗诱导。结论：我们的研究结果表明，局部消融和局部应用免疫刺激剂的组合启动了干扰素特征的激活和B细胞中的抗原呈递，这与乳腺癌的积极临床结果相关。这些发现拓宽了我们对LAIT在重塑TME中的调节作用的理解，并阐明了B细胞活化在临床应用中的潜力。
Rationale: B cells have emerged as key regulators in protective cancer immunity. However, the activation pathways induced in B cells during effective immunotherapy are not well understood. Methods: We used a novel localized ablative immunotherapy (LAIT), combining photothermal therapy (PTT) with intra-tumor delivery of the immunostimulant N-dihydrogalactochitosan (GC), to treat mice bearing mouse mammary tumor virus-polyoma middle tumor-antigen (MMTV-PyMT). We used single-cell RNA sequencing to compare the transcriptional changes induced by PTT, GC and PTT+GC in B cells within the tumor microenvironment (TME). Results: LAIT significantly increased survival in the tumor-bearing mice, compared to the treatment by PTT and GC alone. We found that PTT, GC and PTT+GC increased the proportion of tumor-infiltrating B cells and induced gene expression signatures associated with B cell activation. Both GC and PTT+GC elevated gene expression associated with antigen presentation, whereas GC elevated transcripts that regulate B cell activation and GTPase function and PTT+GC induced interferon response genes. Trajectory analysis, where B cells were organized according to pseudotime progression, revealed that both GC and PTT+GC induced the differentiation of B cells from a resting state towards an effector phenotype. The analyses confirmed upregulated interferon signatures in the differentiated tumor-infiltrating B cells following treatment by PTT+GC but not by GC. We also observed that breast cancer patients had significantly longer survival time if they had elevated expression of genes in B cells that were induced by PTT+GC therapy in the mouse tumors. Conclusion: Our findings show that the combination of local ablation and local application of immunostimulant initiates the activation of interferon signatures and antigen-presentation in B cells which is associated with positive clinical outcomes for breast cancer. These findings broaden our understanding of LAIT's regulatory roles in remodeling TME and shed light on the potentials of B cell activation in clinical applications.